Abstract
Apolipoprotein E (APOE) is the major cholesterol carrier in the brain, affecting various normal cellular processes including neuronal growth, repair and remodeling of membranes, synaptogenesis, clearance and degradation of amyloid β (Aβ) and neuroinflammation. In humans, the APOE gene has three common allelic variants, termed E2, E3, and E4. APOE4 is considered the strongest genetic risk factor for Alzheimer’s disease (AD), whereas APOE2 is neuroprotective. To perform its normal functions, apoE must be secreted and properly lipidated, a process influenced by the structural differences associated with apoE isoforms. Here we highlight the importance of lipidated apoE as well as the APOE-lipidation targeted therapeutic approaches that have the potential to correct or prevent neurodegeneration. Many of these approaches have been validated using diverse cellular and animal models. Overall, there is great potential to improve the lipidated state of apoE with the goal of ameliorating APOE-associated central nervous system impairments.
Highlights
ApoE, a 34 kDa protein composed of 299 amino acids, is a member of the superfamily of amphiphilic exchangeable apolipoproteins
While cerebrospinal fluid (CSF) derived from ABCG1 −/− mice has increased levels of amyloid β (Aβ)(1-42) compared to wild-type mice [51], overexpressing ABCG1 did not alter the levels of Aβ, plaques, apolipoprotein E (apoE) levels, cholesterol efflux, or cognitive performance in mouse models of Alzheimer’s disease (AD) [52]
ApoE is the main lipid carrier in the central nervous system (CNS) and the current evidence highlights the importance of Apolipoprotein E (APOE) isoforms in modulating the pathogenesis of AD
Summary
We will first consider the role of apolipoprotein E (apoE) in lipid homeostasis in the central nervous system (CNS). We will summarize data on the effects of APOE genotype on apoE function and lipid trafficking in normal functions and in pathogenesis. We will speculate on ways to increase lipidation of apoE with the goal to decrease apoE-associated CNS impairments
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